Hyperthermia aggravates status epilepticus-induced epileptogenesis and neuronal loss in immature rats.

This study tightly controlled seizure duration and severity during status epilepticus (SE) in postnatal day 10 (P10) rats, in order to isolate hyperthermia as the main variable and to study its consequences. Body temperature was maintained at 39 ± 1 °C in hyperthermic SE rats (HT+SE) or at 35 ± 1 °C in normothermic SE animals (NT+SE) during 30 min of SE, which was induced by lithium-pilocarpine (3 mEq/kg, 60 mg/kg) and terminated by diazepam and cooling to NT. All video/EEG measures of SE severity were similar between HT+SE and NT+SE pups. At 24h, neuronal injury was present in the amygdala in the HT+SE group only, and was far more severe in the hippocampus in HT+SE than NT+SE pups. Separate groups of animals were monitored four months later for spontaneous recurrent seizures (SRS). Only HT+SE animals developed convulsive SRS. Both HT+SE and NT+SE animals developed electrographic SRS (83% vs. 55%), but SRS frequency and severity were higher in hyperthermic animals (12.5 ± 3.5 vs. 4.2 ± 2.0 SRS/day). The density of hilar neurons was lower, thickness of the amygdala and perirhinal cortex was reduced, and lateral ventricles were enlarged in HT+SE over NT+SE littermates and HT/NT controls. In this model, hyperthermia greatly increased the epileptogenicity of SE and its neuropathological sequelae.

Convulsant action of systemically administered glutamate and bicuculline methiodide in immature rats.

Developmental changes of transport of drugs into the brain play an important role in ontogenetic neuropharmacology. Two convulsant drugs with different mechanisms of action (glutamate and bicuculline methiodide) were chosen to demonstrate these changes in developing rats. High dose of glutamate (4 g/kg i.p.) induced both minimal (predominantly clonic) and generalized tonic-clonic seizures in rat pups 7, 12, and 18 days old. In contrast, seizures were only exceptionally observed in 25 and 90 days old animals. Bicuculline methiodide was administered in a dose of 2 or 20 mg/kg i.p. The first sign of bicuculline methiodide action in all age groups was represented by automatisms, a symptomatology never seen after bicuculline hydrochloride administration. Minimal seizures were induced in 12-day-old and in a few 18-day-old and adult rats. Generalized seizures were common after the higher dose of bicuculline methiodide in 7- and 12-day-old rat pups, seldom in 18-day-old ones and never seen in 25-day-old and adult animals. Both glutamate and bicuculline methiodide enter the brain in immature rats but the mechanisms are probably different - glutamate is transported actively through the blood-brain barrier whereas no similar system is known for bicuculline methiodide.

Suppression of cortical epileptic afterdischarges in developing rats by anticonvulsants increasing GABAergic inhibition.

The anticonvulsant action of three drugs facilitating GABAergic inhibition by different mechanisms (valproate, phenobarbital and progabide) was studied in 229 young rats (12, 18 and 25 days old) with implanted electrodes. Epileptic afterdischarges (ADs) elicited by electrical stimulation of the sensorimotor cortex were used as a model. All three drugs were able to suppress ADs, even the lowest doses used blocked the prolongation seen with repeated stimulations under control conditions. In addition to these general effects, some differences among the three drugs were observed: phenobarbital (10, 20, and 40 mg/kg i.p.) exhibited marked anticonvulsant action in all three age groups whereas valproate (200 and 400 mg/kg i.p.) was somewhat less effective in the youngest rats studied than in the two older groups. Progabide exhibited an effect similar to valproate when a higher dose (150 mg/kg i.p.) was taken into account, but the lower dose (75 mg/kg i.p.) was most efficient in 12 day old rat pups. Our data support the possibility that cortical ADs represent a model of human myoclonic seizures. In addition, they suggest an uneven development of individual components of the GABAergic inhibitory system.

Effects of clonazepam on paired-pulse and frequency potentiation of evoked potentials in rats.

Three different monosynaptic evoked potentials (thalamocortical, interhemispheric, i.e. transcallosal, and entorhino-dentate) were used to study the paired-pulse and frequency potentiation in adult rats. A marked potentiation was seen in both neocortical responses under control conditions (up to 200%), whereas potentiation in the dentate gyrus was only moderate. Clonazepam (0.1 and/or 1 mg/kg, i.p.) antagonized the potentiation of the thalamocortical responses only, the frequency potentiation was suppressed in a dose-dependent manner, and the paired-pulse potentiation was significantly attenuated only by the higher dose of clonazepam. The potentiation of the cortical interhemispheric as well as of the entorhino-dentate evoked potentials was not changed by either dose of clonazepam. The present results do not form the hypothesis of frequency potentiation as a mechanism of epileptogenesis.